The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo

Fungal corneal ulcers tend to have very poor outcomes with commonly used treatments. There
has only been a single randomized trial of anti-fungal therapy for mycotic keratitis, and no
new ocular anti-fungal medications have been approved by the FDA since the 1960s. The
triazole voriconazole has recently become the treatment of choice for systemic fungal
infections such as pulmonary aspergillosis. The use of topical ophthalmic preparations of
voriconazole has been described in numerous case reports, however there has been no
systematic attempt to determine whether it is more or less clinically effective than
natamycin. Additionally, there have been many case reports of the use of oral voriconazole in
the treatment of fungal corneal ulcers, however there has been no systematic attempt to
determine if it improves outcomes in severe ulcers.

This study is a randomized, double-masked, placebo-controlled trial to determine if the use
of oral voriconazole in severe ulcers reduces the rate of perforations. 240 fungal corneal
ulcers with baseline visual acuity worse than 6/120 presenting to the Aravind Eye Hospitals
and the UCSF Proctor Foundation will be randomized to receive oral voriconazole plus topical
voriconazole and topical natamycin, or oral placebo plus topical voriconazole and topical
natamycin. The primary outcome is the rate of perforation over the three month follow-up
period.

Inclusion Criteria:

- Presence of a corneal ulcer at presentation

- Evidence of filamentous fungus on smear (KOH wet mount, Giemsa, or Gram stain)

- Visual acuity worse than 6/120 (20/400, logMAR 1.3)

- The patient must be able to verbalize a basic understanding of the study after it is
explained to the patient, as determined by physician examiner. This understanding must
include a commitment to return for follow-up visits.

- Willingness to be treated as an inpatient or to be treated as an outpatient and return
every 3 days +/- 1 day until re-epithelialization and every week to receive fresh
medication for 3 weeks

- Appropriate consent

Exclusion Criteria:

- Evidence of bacteria on Gram stain at the time of enrollment

- Evidence of acanthamoeba by stain

- Evidence of herpetic keratitis by history or exam

- Corneal scar not easily distinguishable from current ulcer

- Age less than 16 years (before 16th birthday)

- Bilateral ulcers

- Previous penetrating keratoplasty in the affected eye

- Pregnancy (by history or urine test) or breast feeding (by history)

- Known liver disease, including hepatitis or cirrhosis (Child-Pugh A-C)

- Acuity worse than 6/60 (2/200) in the fellow eye (note that any acuity, uncorrected,
corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment)

- Acuity better than 6/120 (20/400) in the study eye (note that any acuity, uncorrected,
corrected, pinhole, or BSCVA can be used for enrollment)

- Currently on rifampin, rifabutin, ritonavir, long acting barbiturates, phenytoin,
carbamazepine, or other drugs known to interact with voriconazole

- Known allergy to study medications (antifungal or preservative)

- No light perception in the affected eye

- Not willing to participate